PROJECT SUMMARY/ABSTRACT Metabolic diseases, such as diabetes and obesity, affect millions of individuals in the United States leading to significant morbidity and mortality. While intensive lifestyle intervention and bariatric surgery are common treatment approaches, lifestyle intervention is not typically durable in the long term, and surgical procedures carry the risk of complications. Hence, there is a critical need to identify novel druggable targets to effectively treat diabetes and obesity. G protein?coupled receptors (GPCRs) regulate important physiological functions through a diverse array of ligands and are the most successful class of druggable targets. Therefore, elucidating the physiological function of GPCRs in key metabolic organs holds promise to the development of novel therapeutics for metabolic diseases. In recent years, gastrointestinal (GI) tract has become an emerging therapeutic target for metabolic disease therapy. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are gut hormones secreted by the enteroendocrine cells in the gut to regulate glucose metabolism and energy balance via endocrine and neural mechanisms. The release of incretin hormones is tightly regulated by G protein-coupled receptors (GPCRs) and their cognate ligands. However, pathways regulating endogenous gut hormone secretion are not completely understood. We recently discovered that GPR17 is expressed in the GLP-1 (but not GIP)-producing cells in human gut. The overall goal of this proposal is to elucidate the metabolic function of Gpr17 in the GI tract. Our preliminary data showed that loss of Gpr17 in gut epithelium leads to improved glucose tolerance with increased glucose- stimulated insulin and GLP-1 (but not GIP) secretion. Gpr17 gut knockout mice also exhibit increased satiety during fasting-refeeding challenge. Based on our preliminary data, we hypothesize that inhibiting Gpr17 function in the gut improves glucose homeostasis and increases satiety via modulating enteroendocrine cellular function and gut hormone release. To test our hypothesis, we propose the following studies. In Aim 1, we will determine the role of intestinal epithelial Gpr17 in glucose homeostasis by measuring nutrient-stimulated GLP-1 and other gut hormone secretion and systemic insulin sensitivity. In Aim 2, we will determine the role of intestinal Gpr17 in satiety regulation by examining the effects on gut physiology and vagal sensory system. In Aim 3, we will functionally characterize Gpr17 signaling and identify molecular mechanisms to potentiate GLP-1 secretion in enteroendocrine cells. Our preliminary data and the demonstrated availability of in vitro and in vivo models support the feasibility of our proposed study. Upon successful completion of this proposal, we expect to determine the metabolic effect of Gpr17 signaling in the gut on systemic glucose metabolism and satiety regulation. These studies will lay the foundation for identifying novel molecules that target Gpr17 in the brain-gut axis for the development of potential therapeutic approaches.